It is known that sigma receptors are expressed in central nervous cells, etc., and adjust a number of biological mechanisms involved in neurodegeneration (Non Patent Literature 1). Two subtypes of sigma receptors (sigma 1 and sigma 2) are known, and they can be distinguished by different pharmacological profiles and molecular characteristics.
Sigma-1 receptors are present in the nucleus of the central nervous system, several types of central nervous cells (astrocytes, microglia, and oligodendrocytes), and the central nervous system-related immune and endocrine tissues. The receptors are considered to be involved in a plurality of physiological and pathological pathways. However, the roles of sigma-1 receptors in the individual pathways have not yet been elucidated.
Sigma-2 receptors have been identified also in central nervous cells and are largely present, especially in proliferating cells or tissues of tumors, etc. The receptors are considered to regulate the growth of tumor cells (Non Patent Literature 2). Meanwhile, it has also been reported that sigma-2 receptors are involved in adhesion to amyloid beta cells (Non Patent Literature 3).
Known sigma-1 receptor antagonists are BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and NE-100 (4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzene ethaneamine). Meanwhile, known sigma-1 receptor agonists are (+)-pentazocine, (+)-SKF10,047 (N-allylnormetazocine), PRE084 (2-morpholin-4-ylethyl-1-phenylcyclohexane-1-carboxylate), and SA4503 (1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine). Many commercially available drugs (e.g., haloperidol, donepezil, and fluvoxamine) interact with sigma-1 receptors. However, there are not many publicly known compounds which selectively have a high affinity for the sigma-1 receptor.
It is widely known that many of sigma-1 receptor ligands bind to sigma-2 receptors. The same applies to many of the compounds described above. Meanwhile, sigma-2-receptor-selective ligands, such as Siramesine (1′-{4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl}-3H-spiro[2-benzofuran-1,4′-piperidine]), and PB28(1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine), have been developed.
To date, it has been known that alkyl ether derivatives described in Patent Literature 1 and 2 have the neuroprotective action, neuroregenerative action, neurite outgrowth-promoting action, and neurogenesis-inducing action.